Ethanol has been recognized as an important immunomodulatory factor, associated with weakened immune response. Acute ethanol exposure has been shown to adversely affect the functions of macrophages (M(I)), components of innate immune system. Toll-like receptors (TLRs), expressed by M(I),are crucial in the recognition of microbial pathogens, and in triggering of immune responses. Even though TLRs activate highly homologous intracellular signaling pathways, the resulting biological responses are diverse. The purpose of this study is to characterize the effects of acute ethanol exposure on M(I)inflammatory responses triggered by different TLR ligands. The hypothesis is that ethanol alters the TLR-mediated signaling in macrophages, which leads to inhibition of pro-inflammatory cytokine production. To address this hypothesis, the effects of acute ethanol on TLR ligands-stimulated activation of mitogen-activated protein kinases (MAPKs) and production of pro-inflammatory cytokines will be examined. Aim I will determine whether acute ethanol exposure affects pro-inflammatory cytokine production by murine macrophages stimulated with LPS (TLR4 ligand). Aim II will determine whether ethanol affects macrophage MAPK activation. Aim III will characterize the effect of ethanol on M(I)MAPK activation and pro-inflammatory cytokine production upon various TLR ligands stimulation. This proposal has the potential to elucidate the mechanism(s) behind the immunomodulatory effects of ethanol. Multiple reports indicate that its moderate use is linked to a reduction of the risk for coronary heart disease and stroke. Since there is also growing evidence that inflammation is a contributing factor in etiology of these diseases, it is plausible to consider that a positive effect of ethanol on cardiovascular system may result from its anti-inflammatory action. [unreadable] [unreadable]